Inflammation is an important component in the progression of colon cancer. Tumor inflammation is observed in sporadic colorectal cancer (CRC) as well as colitis-associated colon cancer (CAC). However, it is still unclear if preexisting inflammation that is evident in CAC or inflammation that is observed in sporadic CRC play unique or overlapping roles in cancer progression. Hypoxia is a noted feature in most solid tumors and mediates a response through activation of transcription factors, hypoxia-inducible factor (HIF)1a and HIF2a. HIF1a and HIF2a are essential in regulating tumor cell metabolism, nutrient uptake, angiogenic response, cell survival and proliferation. Recently we show that HIF2a is rapidly activated in inflamed and tumor mucosa and in many cases precedes tissue hypoxia. Activation of HIF2a (but not HIF1a) induces an epithelial-elicited inflammatory response, which plays an important role in colon cancer progression. HIF2a activation in inflamed foci leads to an increase in distinct subset of direct target genes. The pro-inflammatory HIF2a response leads to accumulation of myeloid-derived suppressor cells (MDSC), which are important cells in tumor growth. Although our results demonstrate a central role for HIF2a in the molecular link between inflammation and colon tumor progression, details regarding the underlying mechanisms and overlapping and distinct roles in colitis, CAC and CRC are still unclear. We hypothesize that rapid activation of epithelial HIF2a leads to a pro-inflammatory response critical in colon cancer progression through the recruitment and enhanced activity of MDSCs. Our major goals are: (i) identify mechanisms leading to rapid activation of HIF2a in inflamed and tumor mucosa. Our data suggest a novel oncometabolite-mediated activation of HIF2a signaling in inflamed mucosa and this will be tested in colon cancer-derived cell lines, patient-derived adenoma organoid models and mouse models of sporadic CRC and CAC (ii) Characterize precise mechanisms leading to a pro-inflammatory HIF2a response. We have identified myc-associated zinc finger protein (MAZ) as novel factor essential for HIF2a-induced pro-inflammatory target genes. We will further understand precise mechanisms and requirement of MAZ in HIF2a signaling. (iii) Understand how the HIF2a pro-inflammatory response increases colon cancer growth and progression. Tumor inflammation leads to increase in cytokine-mediated growth response and attenuates anticancer immune responses. Epithelial HIF2a is critical in the recruitment and function of MDSCs, a major immune cell critical for immune privilege of tumor cells. We will understand the precise mechanism by which epithelial HIF2a regulates MDSC response in colon tumors. Taken together, the proposed in vivo and in vitro studies will identify fundamental roles of HIF2a in the colon cancer and lay the foundation for pursuing new therapeutic strategies by targeting HIF2a.